Description:
Background:
Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B cell
lymphomas. Frontline treatment does not always work. Researchers want to see if a combination
of drugs can help.
Objective:
To learn if it is safe to give people with certain cancers copanlisib together with rituximab
and combination chemotherapy (DA-EPOCH-R).
Eligibility:
People ages 18 and older with relapsed and/or refractory highly aggressive B-cell lymphomas
such as BL and certain types of DLBCL.
Design:
Participants will be screened with:
Medical history
Physical exam
Bone marrow aspiration and biopsy. A needle will be put into their hipbone. Marrow will be
removed.
Imaging scans of the chest, abdomen, pelvis, and/or brain
Tumor biopsy (if needed)
Blood and urine tests
Heart function tests
Treatment will be given in 21-day cycles for up to 6 cycles. Participants will get copanlisib
by intravenous (IV) infusion. They will also get a group of medicines called DA-EPOCH-R, as
follows. They will get rituximab by IV infusion. Doxorubicin, etoposide, and vincristine will
be mixed together in an IV bag and given by continuous IV infusion over 4 days. They will get
cyclophosphamide by IV infusion. They will take prednisone by mouth.
Participants will have frequent study visits. At these visits, they will repeat some
screening tests. They may give tissue, saliva, and cheek swab samples. They will have at
least one spinal tap. For this, a needle will be inserted into the spinal canal. Fluid will
be removed.
Participants will have a visit 30 days after treatment ends. They will have follow-up visits
for at least 5 years.
Title
- Brief Title: Copanlisib With Dose-Adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
- Official Title: Phase 1 Study of Copanlisib With Dose-adjusted EPOCH-R in Relapsed and Refractory Burkitt Lymphoma and Other High-Grade B-cell Lymphomas
Clinical Trial IDs
- ORG STUDY ID:
10000193
- SECONDARY ID:
000193-C
- NCT ID:
NCT04933617
Conditions
- Burkitt Lymphoma
- High-grade B-cell Lymphoma
- T-cell/Histocyte-rich Large B-cell Lymphoma
- Diffuse Large B-Cell Lymphoma (DLBCL)
- Germinal Center B-cell Type (GCB)
Interventions
Drug | Synonyms | Arms |
---|
Rituximab | | 1- Dose Escalation |
Etoposide | | 1- Dose Escalation |
Copanlisib | | 1- Dose Escalation |
Cyclophosphamide | | 1- Dose Escalation |
Doxorubicin | | 1- Dose Escalation |
Vincristine | | 1- Dose Escalation |
Prednisone | | 1- Dose Escalation |
Purpose
Background:
Burkitt Lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) are aggressive B cell
lymphomas. Frontline treatment does not always work. Researchers want to see if a combination
of drugs can help.
Objective:
To learn if it is safe to give people with certain cancers copanlisib together with rituximab
and combination chemotherapy (DA-EPOCH-R).
Eligibility:
People ages 18 and older with relapsed and/or refractory highly aggressive B-cell lymphomas
such as BL and certain types of DLBCL.
Design:
Participants will be screened with:
Medical history
Physical exam
Bone marrow aspiration and biopsy. A needle will be put into their hipbone. Marrow will be
removed.
Imaging scans of the chest, abdomen, pelvis, and/or brain
Tumor biopsy (if needed)
Blood and urine tests
Heart function tests
Treatment will be given in 21-day cycles for up to 6 cycles. Participants will get copanlisib
by intravenous (IV) infusion. They will also get a group of medicines called DA-EPOCH-R, as
follows. They will get rituximab by IV infusion. Doxorubicin, etoposide, and vincristine will
be mixed together in an IV bag and given by continuous IV infusion over 4 days. They will get
cyclophosphamide by IV infusion. They will take prednisone by mouth.
Participants will have frequent study visits. At these visits, they will repeat some
screening tests. They may give tissue, saliva, and cheek swab samples. They will have at
least one spinal tap. For this, a needle will be inserted into the spinal canal. Fluid will
be removed.
Participants will have a visit 30 days after treatment ends. They will have follow-up visits
for at least 5 years.
Detailed Description
Background:
Burkitt Lymphoma (BL) is a highly aggressive B-cell lymphoma that often involves the bone
marrow and central nervous system (CNS)
Frontline therapy cures 80-85% of adults with BL but patients with CNS involvement or those
who relapse after frontline therapy are at high risk for treatment failure
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of aggressive B-cell lymphomas
that are successfully cured by frontline therapy in 60-70% of cases
A subset of DLBCL that have MYC gene rearrangement as well as those that have transformed
from an underlying indolent lymphoma have a lower cure rate
Dose-adjusted (DA)-EPOCH-R is an infusional chemotherapy platform often used as frontline
therapy for these aggressive B-cell lymphomas and is an effective chemotherapy platform from
which to rationally design novel therapies for patients with BL, high grade B-cell lymphomas-
double hit/triple hit (HGBCL-DH/TH), DLBCL and MYC rearrangements, and other high-risk DLBCL
The phosphoinositide 3-kinase (PI3K) pathway is an important signaling pathway for cellular
responses to growth factors and a downstream event of B-cell receptor signaling.
Copanlisib targets both PI3K-a and PI3K-d isoforms and is approved for relapsed FL, active as
monotherapy in DLBCL, and highly effective in pre-clinical models of BL
Copanlisib crosses the blood brain barrier suggesting it may prevent secondary CNS spread in
highly aggressive B-cell lymphomas.
Copanlisib is a rational targeted agent to be added to DA-EPOCH-R in patients with BL,
HGBCL-DH/TH, and other high-risk B-cell lymphomas.
Objective:
To determine the Maximal tolerated dose (MTD) and Recommended Phase II dose (RP2D) of
copanlisib in combination with DA-EPOCH-R in subjects with Burkitt lymphoma (BL) and high
grade B-cell lymphomas- double hit/triple hit (HGBCL-DH/TH) relapsed after or refractory to
chemo-immunotherapy
Eligibility:
Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology, NCI with
one of the following subtypes and prior therapy, as follows:
Burkitt lymphoma, Burkitt-like lymphoma with 11q aberration, High-grade B-cell lymphoma, NOS,
High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements following at least 1
anthracycline-containing regimen
OR
DLBCL, NOS, Germinal center B-cell type (GCB) type, T-cell/histocyte-rich large B-cell
lymphoma, following at least 1 anthracycline-containing regimen AND at least 2 prior regimens
OR be primary refractory to frontline therapy
Age greater than or equal to 18
ECOG performance status 0-2
Adequate bone marrow and organ function
Design:
Phase 1, open-label, single center, non-randomized
3+3 dosing will be used to determine the RP2D and MTD of dose escalated copanlisib in
combination with standard regimen DA-EPOCH-R
Maximum 6 cycles (21-day cycles) of combination therapy
Dose expansion at the RP2D or MTD to evaluate efficacy and further evaluate safety
To explore all dose levels, including further evaluation in dose expansion cohort, the
accrual ceiling will be set at 34
Trial Arms
Name | Type | Description | Interventions |
---|
1- Dose Escalation | Experimental | Copanlisib (IV) per dose level (30 mg, 45 mg, or 60 mg) on days 1 and 5 of each 21-day cycle in combination with standard dosing DA-EPOCH-R to determine RP2D and MTD of copanlisib. Up to 6 cycles total. | - Rituximab
- Etoposide
- Copanlisib
- Cyclophosphamide
- Doxorubicin
- Vincristine
- Prednisone
|
2 - Dose Expansion | Experimental | Copanlisib (IV) at the RP2D or MTD on days 1 and 5 of each 21-day cycle in combination with standard dosing DA-EPOCH-R. Up to 6 cycles total. | - Rituximab
- Etoposide
- Copanlisib
- Cyclophosphamide
- Doxorubicin
- Vincristine
- Prednisone
|
Eligibility Criteria
- INCLUSION CRITERIA:
- Subjects must have a histologic diagnosis, confirmed by the Laboratory of Pathology,
NCI with one of the following subtypes and prior therapy, as follows:
- At least 1 anthracycline-containing regimen:
- Burkitt lymphoma
- Burkitt-like lymphoma with 11q aberration
- High-grade B-cell lymphoma, NOS
- High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements
OR
--Must have had at least 2 prior regimens, 1 of which must have been
anthracyclinecontaining regimen OR be primary refractory to frontline therapy:
---DLBCL, NOS, Germinal center B-cell type (GCB) type;
NOTE: subjects with coexisting or a history of indolent lymphoma are eligible (i.e.,
transformed lymphoma )
---T-cell/histocyte-rich large B-cell lymphoma
- Measurable or evaluable disease on imaging scans or bone marrow
- No other current systemic anti-lymphoma therapy. NOTE: Recent short-term (less than or
equal to 7 days) use of corticosteroids or prior radiation to sites of disease
involvement is permitted.
- Any HIV status will be included in this study as long as infection is controlled; in
the opinion of the investigator. Status must be confirmed at screening and the subject
must be willing to take any recommended antiretroviral therapy.
- Greater than or equal to 18 years of age on day of signing informed consent
- ECOG performance status less than or equal to 2
- Adequate organ function as evidenced by the following laboratory parameters, unless
dysfunction is secondary to lymphoma involvement as determined by the investigator:
- Absolute neutrophil count (ANC) greater than or equal to 1,000 /mm3
- Platelets greater than or equal to 75 x 109 /L
- Hemoglobin greater than or equal to 8 g/dL (unless due to disease itself,
transfusion permitted to meet criteria)
- Renal function Glomerular filtration rate (GFR) >40ml/min/1.73 m2 as estimated by
Modification of Diet in Renal Disease
(MDRD) abbreviated formula. If not on target, a 24- hour urine creatinine clearance can be
used to directly measure.
- Total bilirubin less than or equal to 1.5 x ULN OR < 1.5-3.0 x ULN for subjects with
liver involvement*
- AST and ALT less than or equal to 3.0 x ULN OR < 5 x ULN for subjects with liver
involvement
- Acceptable range as long as there is no persistent nausea, vomiting, right upper
quadrant pain or tenderness, fever, rash, or eosinophilia
- Must have fully recovered from all effects of prior surgery. NOTE: Minor
procedures requiring Twilight sedation, such as tissue biopsies, endoscopies
or mediport placement require a 24-hour waiting period prior to treatment
initiation.
- Women of childbearing potential (WOCBP) and men must agree to use effective
contraception when sexually active. This applies for the time period between
signing of the informed consent form and for at least 3 months after the
last dose of copanlisib and 12 months after the last dose of rituximab,
whichever is later. Women of childbearing potential must have a serum
pregnancy test performed a maximum of 7 days before start of treatment, and
a negative result must be documented before start of treatment.
NOTE: A woman is considered of childbearing potential, (i.e., fertile), following menarche
and until becoming post-menopausal unless permanently sterile. Permanent sterilization
methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral
oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months
without an alternative medical cause. A high follicle stimulating hormone (FSH) level in
the postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy. The investigator or a designated
associate is requested to advise the subject how to achieve highly effective birth control
(failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine
hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual
abstinence. The use of condoms by male subjects is required unless the female partner is
permanently sterile.
- Willingness to have a central venous access line placed if the subject does not
already have one in place
- Ability of patient to understand and the willingness to sign a written informed
consent document
EXCLUSION CRITERIA:
- Subjects previously exposed to, intolerant of, or ineligible for PI3K inhibitors
and/or their combination
- Brain parenchymal involvement
- CMV-positive PCR at screening
- History of diabetic ketoacidosis
- Uncontrolled intercurrent illness including, but not limited to the following that may
limit interpretation of results or that could increase risk to the subject at the
discretion of the investigator:
- Any secondary malignancy that requires active systemic therapy
- Diabetes mellitus with Hgb A1C > 8.5
- Clinically significant interstitial lung disease and/or lung disease that severly
impairs lung function
- Uncontrolled HIV
- Active hepatitis C infection. NOTE: Subjects who are hepatitis C antibody
positive will need to have a negative HCV PCR result before enrollment. Those
with a positive PCR for hepatitis C are excluded.
- Active hepatitis B infection. NOTE: Patients who are hepatitis B surface antigen
(HbcsAg) or hepatitis B core antibody (HbcAb) positive will need to have a
negative HBV PCR result before enrollment. Those with a positive PCR for
hepatitis B are excluded. Those who are hepatitis B surface antigen (HbcsAg) or
hepatitis B core antibody (HbcAb) positive with a negative PCR for hepatitis B
will be treated with antivirals designed to prevent hepatitis B reactivation
(e.g., entecavir) throughout therapy and for 12 months after therapy and have
monitoring for hepatitis B reactivation with PCR.
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization
abnormalities, including any of the following:
- History of acute coronary syndromes (including myocardial infarction,
unstable angina, coronary artery bypass grafting, coronary angioplasty, or
stenting) or symptomatic pericarditis within 6 months prior to screening
- Congestive heart failure (New York Heart Association functional
classification III-IV)
- Unstable angina
- Left Ventricular Ejection Fraction (LVEF) <40% as determined by
echocardiogram (ECHO) at screening
- Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia),
complete left bundle branch block, high-grade AV block (e.g., bifascicular
block, Mobitz type II and third-degree AV block)
- Long QT syndrome or family history of idiopathic sudden death or congenital
long QT syndrome, or any of the following:
- Long QT syndrome or family history of idiopathic sudden death or
congenital long QT syndrome, or any of the following:
- Inability to determine the QT interval on screening (QTcF, using
Fredericia s correction)
- Long QT syndrome or family history of idiopathic sudden death or
congenital long QT syndrome
- Known mental or physical illness that would interfere with cooperation with the
requirements of the trial or confound the results or interpretation of the
results of the trial and, in the opinion of the treating investigator, would make
the subject inappropriate for entry into the study.
- Requirement to continue on any of the medications that are excluded
- Breast-feeding subjects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with these agents,
breastfeeding should be discontinued if the mother is treated on study.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Maximum tolerated dose (MTD) and Recommended Phase II dose (RP2D) |
Time Frame: | 21 days |
Safety Issue: | |
Description: | Frequency (number and percentage) of treatment emergent adverse events |
Secondary Outcome Measures
Measure: | Overall Response Rate |
Time Frame: | 6 cycles |
Safety Issue: | |
Description: | The response rate will be determined and reported along with a 95% confidence interval |
Measure: | Progression-free survival |
Time Frame: | every 3 months for 2 years, every 6 months for years 2-5 |
Safety Issue: | |
Description: | The response rate will be determined and reported along with a 95% confidence interval |
Measure: | Complete Response Rate |
Time Frame: | every 3 months for 2 years, every 6 months for years 2-5 |
Safety Issue: | |
Description: | The response rate will be determined and reported along with a 95% confidence interval |
Measure: | Overall survival (OS) |
Time Frame: | every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually |
Safety Issue: | |
Description: | The response rate will be determined and reported along with a 95% confidence interval |
Measure: | Event-free survival (EFS) |
Time Frame: | every 2 months for 6 months, every 3 months for 2 years, every 6 months for 2 years, then annually |
Safety Issue: | |
Description: | The response rate will be determined and reported along with a 95% confidence interval |
Measure: | Safety and tolerability |
Time Frame: | 6 cycles |
Safety Issue: | |
Description: | rate and severity of AEs will be summarized by grade and type of toxicity |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Aliqopa
- BAY 80-6946
- Monoclonal Antibody
- PI3K Target
Last Updated
September 1, 2021